US4978775A - Process for producing bicyclo[3.3.0]octanes - Google Patents

Process for producing bicyclo[3.3.0]octanes Download PDF

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Publication number
US4978775A
US4978775A US06/890,690 US89069086A US4978775A US 4978775 A US4978775 A US 4978775A US 89069086 A US89069086 A US 89069086A US 4978775 A US4978775 A US 4978775A
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alkyl group
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US06/890,690
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Shiro Ikegami
Yasuhiro Torizawa
Seizi Kurozumi
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Teijin Ltd
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Teijin Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • This invention relates to a process for producing bicyclo[3.3.0] octanes. More particularly, this invention relates to an industrially advantageous process for producing isocarbacyclins or their synthetical intermediates, bicyclo[3.3.0] octanes.
  • Carbocyclines are stable compounds of prostaglandin I 2 and are very useful compounds as an antithrombotic agent. It has recently been found that 9(0)-methano- ⁇ 6 -(9 ⁇ )-prostaglandin I 1 (isocarbacyclin) is a compound which displays the strongest anticoagulant action against thrombocyte coagulation among the analogues of carbocycline and is expected to be used as medicine (Ikegami et al., Tetrahedron Lett., 33, 3493 (1983); ibid., 33, 3497, (1983); European Laid-Open Patent Publication No. 0134246).
  • a primary object of this invention is to provide an industrially advantageous process for producing isocarbacyclins.
  • Another object of this invention is to provide an industrially excellent process for producing synthetic intermediates of isocarbacyclins.
  • a further object of this invention is to provide novel synthetic intermediates of isocarbacyclins.
  • C 1 ⁇ C 10 alkyl group such linear or branched groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl, for instance, may be mentioned.
  • the substituted phenyl group may have 1 to 3 substituents as mentioned above, preferably one substituent.
  • tri (C 1 ⁇ C 7 ) hydrocarbon silyl group such tri (C 1 ⁇ C 4 ) alkylsilyl as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl groups; such diphenyl (C 1 ⁇ C 4 ) alkylsilyl as a t-butyldiphenylsilyl group; and tribenzylsilyl group may be mentioned as preferable ones.
  • C 2 ⁇ C 4 alkoxy group methoxy, ethoxy, propoxy, and butoxy, for instance, may be mentioned.
  • substituent group of the phenyl group which may be substituted or the phenoxy group which may be substituted a fluorine atom, methyl, trifluoromethyl, methoxy, and trifluoromethoxy, for instance, may be mentioned.
  • C 2 ⁇ C 9 alkenyl group 2-pentenyl, 4-pentenyl, 2-methyl-3-pentenyl, hexenyl, 1,4-dimethyl-3-pentenyl, and 2,6-dimethyl-5-heptenyl may be mentioned.
  • C 2 ⁇ C 9 alkynyl group 2-butynyl, 2-pentynyl, 3-pentynyl, and 1-methyl-2-pentynyl may be mentioned.
  • C 5 ⁇ C 6 cycloalkyl group cyclopentyl and cyclohexyl, for instance, may be mentioned.
  • organic tin compound like this, trimethyltin hydride, triethyltin hydride, tri-n-butyltin hydride, tri-n-hexyltin hydride, tri-n-octyltin hydride, and triphenyltin hydride, for instance, may be mentioned. Of these, tri-n-butyltin hydride and triphenyltin hydride are preferable, and tri-n-butyltin hydride is especially preferable. It is advisable to use the organic tin compound in coexistence with a radical generating agent.
  • a radical generating agent As the radical generating agent, ⁇ , ⁇ '-azobisisobutyronitrile, bis-tert-butylperoxide, and tert-butylhydroperoxide are desirably used.
  • the organic tin compound is usually used in 2 to 20 molecular weight, preferably 2 to 5 molecular weight, against 1 molecular weight of the thiol ester compound of formula (I).
  • the radical generating agent is usually used in 0.01 to 0.5 molecular weight, preferably 0.05 to 0.1 molecular weight, against 1 molecular weight of the thiol ester compound of formula (I).
  • reaction it is desirable to carry out the reaction under an inert atmosphere such as nitrogen and argon, usually at 60° to 200° C., preferably at 100° to 150° C.
  • the reaction may also be conducted in an inert organic medium.
  • inert organic media such aromatic hydrocarbons as benzene, toluene, and xylene and such aliphatic hydrocarbons as pentane and hexane may be mentioned and the aromatic hydrocarbons such as benzene and toluene are especially preferable.
  • the deprotecting reaction is a publicly known reaction per se, and in case where the protecting group is a group which forms an acetal bond with a hydrogen atom of the hydroxyl group, the reaction is carried out by use of acetic acid, pyridinium salt of p-toluenesulfonic acid, or cation-exchange resin as a catalyst and by use of water, tetrahydrofuran, ethyl ether, dioxane, acetone, and acetonitrile as a reaction solvent.
  • the hydrolytic reaction is a publicly known reaction per se and it can be carried out, for instance, by use of such an enzyme as lipase in water or in a water-containing solvent at a temperature ranging from -10° C. to +60° C. for 10 minutes to 24 hours.
  • the salt-forming reaction is a publicly known reaction per se and is carried out by allowing carboxylic acid, which is obtained in the aforementioned hydrolytic reaction, to be neutralized with an approximately equivalent weight of a basic compound of sodium hydroxide, potassium hydroxide, or sodium carbonate; ammonia, trimethylamine, monoethanolamine, or morpholine according to an ordinary method.
  • isocarbacyclins which are medicines having a strong anticoagulant action against thrombocyte coagulation and are also useful compounds as the synthetic intermediates of such isocarbacyclins.
  • isocarbacyclins expressed by the following formula (II-1), which are obtained from a thiol ester compound in which R ⁇ in the aforementioned formula (I) is a substituted vinyl group of formula (V), ##STR11## wherein R 11 , R 21 , R 6 , R 7 , and n are as defined hereinabove and R 51 indicates a hydrogen atom or a hydroxyl-protecting group.
  • the reduction of the carbonyl group of the enone compound of the aforementioned formula (VI) is a publicly known reaction per se and K-selectoride, L-selectoride, and sodium boron hydride-cerium thrichloride is especially preferable.
  • the reaction conditions may be laid down according to the methods described in a document, J. Amer. Chem. Soc., 100, 2226 (1978).
  • the allyl alcohol compound of the aforementioned formula (VII) can thus be obtained and then it is made to react with the allylhalothionocarbonate compound of the aforementioned formula (VIII).
  • X in the formula (VIII) is a halogen atom, which includes chlorine and bromine and a chloride atom is especially preferable.
  • allyhalothionocarbonate compound of formula VIII 1.5 to 10 molecular weight, preferably 2 to 4 molecular weight, of allyhalothionocarbonate compound is used against 1 molecular weight of ally alcohol compound.
  • the reaction is usually conducted in such a medium as methylene chloride, tetrahydrofuran, dimethoxyethane, ether, acetonitrile, pyridine, and hexamethylphosphorousamide (HMPA), of which methylene chloride and acetonitrile are used preferably.
  • HMPA hexamethylphosphorousamide
  • trialkylamines as trimethylamine, triethylamine, and diisopropylamine
  • aromatic amines as pyridine, dimethylaminopyridine, and collidine
  • n-butyl lithium, and t-butoxy potassium of which aromatic amines, inclusive of dimethylaminopyridine, and also n-butyl lithium are preferable, and the aromatic amines are especially preferable.
  • the present invention provides a process in which the thiol ester compound of formula (I) is subjected to the reduction reaction to obtain bicyclo[3.3.0] octanes of formula (II) in high yields.
  • the thiol ester compound of formula (I) can be obtained advantageously on an industrial scale by allowing an allyl alcohol compound of formula (VII), which is easily obtained from Corey lactone of formula (IX), to react with an allylhalothionocarbonate compound of formula (VIII).
  • Enone (1) (147 mg, 0.24 mmol) was dissolved in methanol (3 ml) and the solution was cooled to -40° C.
  • CeCl 3 .7H 2 O (90.5 mg, 0.24 mmol, 1 equivalent) was first added to the solution and then NaBH 4 (11.0 mg, 0.29 mmol, 1.2 equivalents) was further added thereto little by little with stirring.
  • the reaction mixture was stirred under the same conditions for 5 minutes, the mixture was diluted with ether (20 ml). A saturated aqueous solution of NaCl (5 ml) and 10% HCl (one drop) were added thereto and the mixture was stirred for a while.
  • IR liquid film: 3450, 2930, 2850, 1735, 1425, 1110, 700 cm -1 .
  • the manufacturing process proposed by the present invention relates to an industrially excellent process for producing bicyclo[3.3.0] octanes and this invention has made it possible to obtain pharmaceutically useful isocarbacyclins or their synthetic intermediates from the starting materials readily available on the market.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US06/890,690 1984-11-16 1985-11-14 Process for producing bicyclo[3.3.0]octanes Expired - Fee Related US4978775A (en)

Applications Claiming Priority (2)

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JP59240592A JPS61122292A (ja) 1984-11-16 1984-11-16 新規カルバサイクリン中間体の製法
JP59-240592 1984-11-16

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US4978775A true US4978775A (en) 1990-12-18

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US (1) US4978775A (enrdf_load_stackoverflow)
EP (1) EP0201608A4 (enrdf_load_stackoverflow)
JP (1) JPS61122292A (enrdf_load_stackoverflow)
WO (1) WO1986002923A1 (enrdf_load_stackoverflow)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011091181A1 (en) 2010-01-20 2011-07-28 Tolerx, Inc. Immunoregulation by anti-ilt5 antibodies and ilt5-binding antibody fragments
WO2011091177A1 (en) 2010-01-20 2011-07-28 Tolerx, Inc. Anti-ilt5 antibodies and ilt5-binding antibody fragments
WO2014151917A1 (en) 2013-03-14 2014-09-25 Ffe Therapeutics Llc Compositions and methods for treating angiogenesis-related disorders
WO2016210241A1 (en) 2015-06-26 2016-12-29 Beth Israel Deaconess Medical Center, Inc. Cancer therapy targeting tetraspanin 33 (tspan33) in myeloid derived suppressor cells
EP3434694A1 (en) 2010-04-09 2019-01-30 Critical Care Diagnostics, Inc. Soluble human st-2 antibodies and assays
WO2019229658A1 (en) 2018-05-30 2019-12-05 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2019229701A2 (en) 2018-06-01 2019-12-05 Novartis Ag Binding molecules against bcma and uses thereof
WO2020079580A1 (en) 2018-10-15 2020-04-23 Novartis Ag Trem2 stabilizing antibodies
WO2020236792A1 (en) 2019-05-21 2020-11-26 Novartis Ag Cd19 binding molecules and uses thereof
WO2020236797A1 (en) 2019-05-21 2020-11-26 Novartis Ag Variant cd58 domains and uses thereof
WO2020254861A1 (en) 2019-06-19 2020-12-24 Ovatrition Ltd. Antibody-mediated neutralization of beta-lactamases
WO2021053560A1 (en) 2019-09-18 2021-03-25 Novartis Ag Combination therapy with entpd2 and cd73 antibodies
WO2021053559A1 (en) 2019-09-18 2021-03-25 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2021097338A1 (en) 2019-11-15 2021-05-20 Pliant Therapeutics, Inc. Compositions and methods for activation of integrins
WO2022097060A1 (en) 2020-11-06 2022-05-12 Novartis Ag Cd19 binding molecules and uses thereof
WO2022097061A1 (en) 2020-11-06 2022-05-12 Novartis Ag Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies
WO2022162569A1 (en) 2021-01-29 2022-08-04 Novartis Ag Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8429545D0 (en) * 1984-11-22 1985-01-03 May & Baker Ltd Compositions of matter

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0079733A2 (en) * 1981-11-13 1983-05-25 Teijin Limited Process for prostaglandin E1, production and novel delta 7-prostaglandines E and 7-hydroxyprostaglandins E

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0079733A2 (en) * 1981-11-13 1983-05-25 Teijin Limited Process for prostaglandin E1, production and novel delta 7-prostaglandines E and 7-hydroxyprostaglandins E

Non-Patent Citations (6)

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011091177A1 (en) 2010-01-20 2011-07-28 Tolerx, Inc. Anti-ilt5 antibodies and ilt5-binding antibody fragments
WO2011091181A1 (en) 2010-01-20 2011-07-28 Tolerx, Inc. Immunoregulation by anti-ilt5 antibodies and ilt5-binding antibody fragments
EP3848394A1 (en) 2010-04-09 2021-07-14 Critical Care Diagnostics, Inc. Soluble human st-2 antibodies and assays
EP3434694A1 (en) 2010-04-09 2019-01-30 Critical Care Diagnostics, Inc. Soluble human st-2 antibodies and assays
WO2014151917A1 (en) 2013-03-14 2014-09-25 Ffe Therapeutics Llc Compositions and methods for treating angiogenesis-related disorders
WO2016210241A1 (en) 2015-06-26 2016-12-29 Beth Israel Deaconess Medical Center, Inc. Cancer therapy targeting tetraspanin 33 (tspan33) in myeloid derived suppressor cells
WO2019229658A1 (en) 2018-05-30 2019-12-05 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2019229701A2 (en) 2018-06-01 2019-12-05 Novartis Ag Binding molecules against bcma and uses thereof
WO2020079580A1 (en) 2018-10-15 2020-04-23 Novartis Ag Trem2 stabilizing antibodies
WO2020236792A1 (en) 2019-05-21 2020-11-26 Novartis Ag Cd19 binding molecules and uses thereof
WO2020236797A1 (en) 2019-05-21 2020-11-26 Novartis Ag Variant cd58 domains and uses thereof
WO2020254861A1 (en) 2019-06-19 2020-12-24 Ovatrition Ltd. Antibody-mediated neutralization of beta-lactamases
US12384832B2 (en) 2019-06-19 2025-08-12 Christopher Oelkrug Antibody-mediated neutralization of beta-lactamases
WO2021053559A1 (en) 2019-09-18 2021-03-25 Novartis Ag Entpd2 antibodies, combination therapies, and methods of using the antibodies and combination therapies
WO2021053560A1 (en) 2019-09-18 2021-03-25 Novartis Ag Combination therapy with entpd2 and cd73 antibodies
WO2021097338A1 (en) 2019-11-15 2021-05-20 Pliant Therapeutics, Inc. Compositions and methods for activation of integrins
US12134642B2 (en) 2019-11-15 2024-11-05 Pliant Therapeutics, Inc. Antibodies binding to α7β1 integrin antibodies and compositions thereof
WO2022097060A1 (en) 2020-11-06 2022-05-12 Novartis Ag Cd19 binding molecules and uses thereof
WO2022097061A1 (en) 2020-11-06 2022-05-12 Novartis Ag Anti-cd19 agent and b cell targeting agent combination therapy for treating b cell malignancies
WO2022162569A1 (en) 2021-01-29 2022-08-04 Novartis Ag Dosage regimes for anti-cd73 and anti-entpd2 antibodies and uses thereof

Also Published As

Publication number Publication date
WO1986002923A1 (en) 1986-05-22
EP0201608A4 (en) 1987-03-30
EP0201608A1 (en) 1986-11-20
JPS61122292A (ja) 1986-06-10
JPH0251559B2 (enrdf_load_stackoverflow) 1990-11-07

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